The field of the invention is systems and methods for focused ultrasound (“FUS”). More particularly, the invention relates to methods for delivery of a focused ultrasonic pulse (“FUP”) to different points of neuronal circuits within the brain under the guidance of an imaging system, such as magnetic resonance imaging (“MRI”) system.
When a substance such as human tissue is subjected to a uniform magnetic field (polarizing field B0), the individual magnetic moments of the nuclei in the tissue attempt to align with this polarizing field, but precess about it in random order at their characteristic Larmor frequency. If the substance, or tissue, is subjected to a magnetic field (excitation field B1) that is in the x-y plane and that is near the Larmor frequency, the net aligned moment, Mz, may be rotated, or “tipped”, into the x-y plane to produce a net transverse magnetic moment Mxy. A signal is emitted by the excited nuclei or “spins”, after the excitation signal B1 is terminated, and this signal may be received and processed to form an image.
When utilizing these “MR” signals to produce images, magnetic field gradients (Gx, Gy, and Gz) are employed. Typically, the region to be imaged is scanned by a sequence of measurement cycles in which these gradients vary according to the particular localization method being used. The resulting set of received MR signals are digitized and processed to reconstruct the image using one of many well known reconstruction techniques.
The measurement cycle used to acquire each MR signal is performed under the direction of a pulse sequence produced by a pulse sequencer. Clinically available MRI systems store a library of such pulse sequences that can be prescribed to meet the needs of many different clinical applications. Research MRI systems include a library of clinically proven pulse sequences and they also enable the development of new pulse sequences.
The MR signals acquired with an MRI system are signal samples of the subject of the examination in Fourier space, or what is often referred to in the art as “k-space”. Each MR measurement cycle, or pulse sequence, typically samples a portion of k-space along a sampling trajectory characteristic of that pulse sequence. Most pulse sequences sample k-space in a raster scan-like pattern sometimes referred to as a “spin-warp”, a “Fourier”, a “rectilinear”, or a “Cartesian” scan. The spin-warp scan technique employs a variable amplitude phase encoding magnetic field gradient pulse prior to the acquisition of MR spin-echo signals to phase encode spatial information in the direction of this gradient. In a two-dimensional implementation (“2DFT”), for example, spatial information is encoded in one direction by applying a phase encoding gradient, Gy, along that direction, and then a spin-echo signal is acquired in the presence of a readout magnetic field gradient, Gx, in a direction orthogonal to the phase encoding direction. The readout gradient present during the spin-echo acquisition encodes spatial information in the orthogonal direction. In a typical 2DFT pulse sequence, the magnitude of the phase encoding gradient pulse, Gy, is incremented, ΔGy, in the sequence of measurement cycles, or “views” that are acquired during the scan to produce a set of k-space MR data from which an entire image can be reconstructed.
An image is reconstructed from the acquired k-space data by transforming the k-space data set to an image space data set. There are many different methods for performing this task and the method used is often determined by the technique used to acquire the k-space data. With a Cartesian grid of k-space data that results from a 2D or 3D spin-warp acquisition, for example, the most common reconstruction method used is an inverse Fourier transformation (“2DFT” or “3DFT”) along each of the 2 or 3 axes of the data set. With a radial k-space data set and its variations, the most common reconstruction method includes “regridding” the k-space samples to create a Cartesian grid of k-space samples and then perform a 2DFT or 3DFT on the regridded k-space data set. In the alternative, a radial k-space data set can also be transformed to Radon space by performing a 1DFT of each radial projection view and then transforming the Radon space data set to image space by performing a filtered backprojection.
Functional magnetic resonance imaging (“fMRI”) technology provides an approach to study neuronal activity. Conventional fMRI detects changes in cerebral blood volume, flow, and oxygenation that locally occur in association with increased neuronal activity induced by functional paradigms. An MRI system is used to acquire signals from the brain over a period of time. As the brain performs a task, these signals are modulated synchronously with task performance to reveal which regions of the brain are involved in performing the task. The series of fMRI time course images must be acquired at a rate that is high enough to see the changes in brain activity induced by the functional paradigm. In addition, because neuronal activity may occur at widely dispersed locations in the brain, a relatively large 3D volume or multi-slice volume must be acquired in each time frame.
With advances in brain imaging techniques, the pathophysiology of psychiatric and medical disorders began to be more and more related to the specific underlying neuronal circuits. Neuronal circuits are specific brain centers that are functionally and anatomically connected with each other. Usually, a circuit involves sub-cortical neuronal centers connected with cortex. While it is not entirely clear how these circuits operate, it is clear that they play a major role in multiple psychiatric, neurological, and medical conditions. For example, obsessive compulsive disorder (“OCD”) and OCD spectrum disorders including impulse control disorders appear to be related to abnormalities in orbito-fronto-thalamic-striatum circuits. Likewise, panic disorder, social anxiety disorder, and panic spectrum disorders seem to be associated with the abnormal functioning of circuits involving orbital-frontal cortex, the amygdala, the cingulum and the hippocampus. Post-traumatic stress disorders seem to associate with abnormalities in prefrontal cortex, the amygdala, and the hippocampus. Psychotic disorders seem to have an association with prefrontal cortex-thalamic-striatum and occipital cortex circuits. Circuits involved in neurological conditions have also been identified. For example, Parkinson's disease, Huntington's disease, Tourette syndrome, and tick syndromes seem to have abnormalities in cortico-thalamic-straitum circuits. Chronic pain has association with cortico-thalamic circuits. Insomnia has association with temporal cortex-lymbic-cingulum circuits. Medical conditions seem to have connection with specific neurocircuitry. For example, obesity and stress are associated with temporal-hypothalamic circuits. For a simple review and description of the above circuits, see the studies described by D. L. Clark and N. N. Boutros in The Brain and Behavior: An Introduction to Behavioral Anatomy, 1999, and by S. L. Rauch, et al., in “Clinical Neuroimaging in Psychiatry,” Harvard Review of Psychiatry, 1995; 2(6):297-312. In addition, substance abuse, including alcoholism and tobacco consumption, could be alleviated by modulating activation from the mesolimbic dopamine reward pathways.
Neuroimaging techniques exist that permit the assessment of rapid changes in activity of the brain, including functional MRI (“fMRI”), vector electroencephalography (“V-EEG”), and positron emission tomography (“PET”). These techniques, specifically fMRI, are capable of producing real time 3-dimensional maps of brain activity. These techniques merit scientists to study the neuronal circuits involved in pathology of different psychiatric or neurological conditions. However, the study process has been slowed by the absence of reliable activation of these circuits.
An orchestrated interplay among various neural circuitries in brain is responsible for normal neurocognitive behaviors and perception. Aberrant regional brain function, either caused by trauma or pathological conditions, results in a wide spectrum of neurological and neuropsychiatric disorders. Conventional pharmacological approaches have been based modulating the state of neurotransmission, such as, the use of neurotransmitter uptake inhibitors, or cellular excitability, such as, medications used in the seizure control. However, these methods generally lack anatomical specificity. Therefore, selective modification of a regional brain activity is desirable in order to study normal neurophysiology by altering the functional state of the specific component(s) in a neural circuitry-of-interest. The ability to modify regional brain function would also provide unprecedented opportunities in attempt to recover/suppress brain function.
Recently, a few novel methods of the treatment of mental and neurological disorders directed at neuronal circuits have been introduced. These include deep brain stimulation with implanted electrodes, which has been successfully used in OCD, Parkinson's disease, and epilepsy. Furthermore, brain surgery used in the treatment of OCD and depression has shown some success. See New England Journal of Medicine, 2001; 656-663, and R. M. Roth, et al., Current Psychiatry Report, 2001; 3(5):366-372. Because of their invasive nature and possible complications, these methods are reserved for the treatment resistant conditions where other treatments fail. However, the success of these treatments underlines the importance of specific neurocircuits in the pathophysiology of mental and neurological disorders. Furthermore, it underlines the importance of developing non-invasive methods of intervention at the neuronal circuit level.
Several invasive techniques have been developed with an aim of providing means of modulating regional brain function. For example, vagus nerve stimulation (“VNS”), believed to be mediated by modulation of release in neurotransmitters via electrical stimulation of the vagus nerves, has been used in treating epilepsy and depression. Similarly, deep brain stimulation (“DBS”) provides targeted delivery of electrical stimulation by the surgical implantation of microelectrodes. The use of DBS has been implicated in treating essential tremor and Parkinson's disease via subthalamic nucleus (“STN”) and the globus pallidus interna (“GPi”). These methods, while more anatomically specific, rely on surgical application of electrodes, thus accompany potential risk factors.
Recently it has been proposed that neuronal circuits can be assessed and modified non-invasively using transcranial magnetic stimulation (“TMS”). The signal from the brain after the TMS stimulation can be read using MRI. Exemplary methods for doing so have been described, for example, in U.S. Pat. No. 6,198,958, which is herein incorporated by reference in its entirety. The method and device proposed by that patent are currently being implemented in psychiatry and neurology for diagnostic and therapeutic purposes. See M. S. George, et al., Journal of Neuropsychiatry and Clinical Neuroscience (Fall 1996), Vol. 8, no. 4, pp. 373-382. The method, however, has several problems. For example, TMS does not stimulate deep brain centers because it is incapable of penetrating brain tissue deeper than 1-2 centimeters (“cm”). Also, TMS has a large area of focus, on the order of 1 cubic cm or more, which does not permit focused activation of a specific neuronal circuit. Also, there is a problem in using TMS together with fMRI, because TMS produces a magnetic signal that interferes with the magnetic field produced by MRI systems, which in turn negatively affects fMRI images.
Focused ultrasound has been used to modify electrical currents in neuronal tissue. This has been done by a combined application of a magnetic field and an ultrasonic field to neuronal and other tissue in the body. Previous methods propose that modification of electrical currents in neuronal tissue will come from the interaction of the two fields. For example, U.S. Pat. No. 4,343,301, describes generating high energy by intersecting two ultrasound beams within any single fixed point of the body, including the skull. While it is not proven that such an application of ultrasound would do anything except heat or destroy tissue, there is recent evidence that the application of focused ultrasound to brain slices, subjected to simultaneous electrical stimulation, can change the electrical currents in the slices. However, because two ultrasound beams cannot be focused within the skull, as a result of the complexity of bone density and bone structure, it is not possible to focus such a two-beam device in the brain tissue.
Some companies have produced ultrasonic devices that use multiple beams. See, for example, G. T. Clement, et al., Physics in Medicine and Biology (December 2000), Vol. 45, no. 12, pp. 3707-3719. By coordinating the amplitude and the phase of the ultrasound beams generated by multiple sources via computer multi-beam devices, algorithms can be developed to adjust the bone dispersion of the beam and focus the ultrasound within the brain tissue. These devices are to be used, for example, as ultrasonic knives within the brain for the destruction of tumors. However, they cannot be used to modify the electrical and electromagnetic currents within the brain circuits without harming the surrounding tissue.
It would therefore be desirable to provide a system and method for the non-invasive modification of neuronal activity. More particularly, it would be desirable to provide a system and method for the non-invasive modification of neuronal activity in a localized and reversible manner, without damage to the underlying tissue.